EXCEED THE SPACE PROVIDED. The long-rangeobjectiveof this projectis to preventprogressionof diabetic nephropathy, the leading causeof end-stagerenal disease (ESRD). In most patientsdiabeticnephropathyprogresses inexorablyto ESRD despite inhibitionof the renin-angiotensin-aldosteronesystem withangiotensin convertingenzyme inhibitors(ACEIs) or angiotensin II type 1 receptor blockers(ARBs). The specific aims of this proposal are to: 1) recruita multiethnicohortof 72 young adults (ages20-40) withtype 1 (n=36) or type2 (n=36) diabetesand overt nephropathy(defined as a urinealbumin/creatinineratio > 300 mg albumin/g creatinine)and randomize in a doubleblind fashion to a controlgroup consisting of ACEI-based therapy alone (ramipril40 mg once daily) or one of two experimentalgroups: a) ACEI + ARB (ramipril40 mg once dailyplusIosartan100 mg once daily)or b) ACEI + mineralocorticoid receptorantagonist (MRA) (ramipril40 mg oncedaily plusspironolactone25 mg once daily);2) conducta 12-month prospective studyto determine if proteinuriais reducedto a greater extent when eitherthe ARB or MRA is added toACEi-based therapy. This studyis poweredto detecta 40% greater reductionin 24-hour urine albumin/creatinineratioin either experimentalgroupversus control (alpha= 0.05, beta=0.20, repeated measures analysisof variance). Secondaryendpointsto be examinedinclude:(a) serum potassiumand creatinineto assess safety, (b) TGF-beta, as a surrogatemarkerfor ongoingrenal injury,(c) plasma reninactivity,angiotensinII andaldosterone levels and (d) plasma lipids and lipoprotein composition; and 3) perform repeated ambulatory blood pressure monitoring (ABPM) to examine the renoprotective effect of the 3 different regimens at comparable 24-hour BP of < 125/75 mmHg. The deliverables include: 1) documentation of the safety of maximal dose combination therapy; 2) the feasibility of utilizing 24-hr ABPM to establish BP independent renoprotective effects of specific antihypertensive therapies; and 3) provide preliminary data for future large-scale studies to test efficacy and safety of combining ACEi with MIRAtherapy on renal outcomes. PERFORMANCE SITE ========================================Section End===========================================